Cross-education (CE) is the process whereby training with one limb leads to subsequent improvement in performance by the opposite untrained limb. We used multimodal neuroimaging in humans to investigate the mediating neural mechanisms by relating quantitative estimates of functional and structural cortical connectivity to individual levels of interlimb transfer. Resting-state (rs)-fMRI and diffusion weighted imaging (DWI) scans were undertaken before unilateral ballistic wrist flexion training. The rs-fMRI sequence was repeated immediately afterward. The increase in performance of the untrained limb was 83.6% of that observed for the trained limb and significantly greater than that of a control group who undertook no training. Functional connectivity in the resting motor network between right and left supplementary motor areas (SMA) was elevated after training. These changes were not, however, correlated with individual levels of transfer. Analysis of the DWI data using constrained spherical deconvolution-based tractography indicated that fractional anisotropy and apparent fiber density in tracts connecting bilateral SMA were negatively correlated with and predictive of transfer. The findings suggest that interhemispheric interactions between bilateral SMA play an instrumental role in CE and that the structural integrity of the connecting white matter pathways influences the level of transfer.

SIGNIFICANCE STATEMENT Strength or skill training with one limb also brings about improvements in the performance of the opposite, untrained limb. This phenomenon, termed cross-education (CE), has obvious potential for the rehabilitation of functional capacity that has been lost through brain insult or musculoskeletal injury. The neural mechanisms that give rise to CE are, however, poorly understood. We used a combination of neuroimaging methods to investigate the pathways in the human brain that mediate CE. We determined that the supplementary motor area (SMA) plays an important role in the interlimb transfer of performance gains and demonstrate that the quality of the white matter fibers connecting right and left SMA predicts the benefit that an individual derives from CE.